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. 2001 Mar;48(3):397–402. doi: 10.1136/gut.48.3.397

HLA and interleukin 1 gene polymorphisms in primary biliary cirrhosis: associations with disease progression and disease susceptibility

P Donaldson 1, K Agarwal 1, A Craggs 1, W Craig 1, O James 1, D Jones 1
PMCID: PMC1760119  PMID: 11171832

Abstract

BACKGROUND AND AIMS—Twin and family studies suggest that there is a genetic component to primary biliary cirrhosis (PBC) but the genetic associations which have been described are weak with marked variations between centres. PBC is heterogeneous and genetic associations with disease progression may be obscured when the PBC population is analysed only as a whole and not subdivided.
METHODS—We have investigated two candidate gene loci in 164 well characterised patients, 88 (54%) of whom had advanced disease.
RESULTS—There was an increased frequency of the HLA DRB1*0801-DQA1*0401-DQB1*0402 haplotype in patients who had progressed to late stage disease (23% v 2% of controls; p=0000044; odds ratio (OR) 15.5, 95% confidence interval (CI) 3.52-68.4) but not in those with early stage disease (4% v 2%). Patients had a higher frequency of the IL-1B*1,1 genotype and lower frequencies of the IL-1B*1,2 and *2,2 genotypes (p=0.00078; OR 2.37, 95% CI 1.38-4.06), and higher frequency of the IL-1RN*1,1 genotype and lower frequency of the IL-1RN*1,2 genotype (p=0.0011; OR 2.28, 95% CI 1.34-3.89). The difference in the IL-1B*1,1 genotype distribution was most marked in patients with early stage disease (77% v 43% of controls; p=0.000003; OR 4.8, 95% CI 2.31-10) but the IL-1RN genotype distribution was similar in patients with early and late stage disease.
CONCLUSIONS—These data indicate a complex relationship between immunoregulatory genes and PBC. While the IL-1 genes are markers of both disease susceptibility and progression, HLA genes appear to be principally associated with disease progression.


Keywords: human leucocyte antigens; primary biliary cirrhosis; interleukin 1

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Selected References

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  1. Agarwal K., Jones D. E., Daly A. K., James O. F., Vaidya B., Pearce S., Bassendine M. F. CTLA-4 gene polymorphism confers susceptibility to primary biliary cirrhosis. J Hepatol. 2000 Apr;32(4):538–541. doi: 10.1016/s0168-8278(00)80213-5. [DOI] [PubMed] [Google Scholar]
  2. Bach N., Schaffner F. Familial primary biliary cirrhosis. J Hepatol. 1994 Jun;20(6):698–701. doi: 10.1016/s0168-8278(05)80137-0. [DOI] [PubMed] [Google Scholar]
  3. Becker K. G. Comparative genetics of type 1 diabetes and autoimmune disease: common loci, common pathways? Diabetes. 1999 Jul;48(7):1353–1358. doi: 10.2337/diabetes.48.7.1353. [DOI] [PubMed] [Google Scholar]
  4. Becker K. G., Simon R. M., Bailey-Wilson J. E., Freidlin B., Biddison W. E., McFarland H. F., Trent J. M. Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases. Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9979–9984. doi: 10.1073/pnas.95.17.9979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Begovich A. B., Klitz W., Moonsamy P. V., Van de Water J., Peltz G., Gershwin M. E. Genes within the HLA class II region confer both predisposition and resistance to primary biliary cirrhosis. Tissue Antigens. 1994 Feb;43(2):71–77. doi: 10.1111/j.1399-0039.1994.tb02303.x. [DOI] [PubMed] [Google Scholar]
  6. Bioque G., Crusius J. B., Koutroubakis I., Bouma G., Kostense P. J., Meuwissen S. G., Peña A. S. Allelic polymorphism in IL-1 beta and IL-1 receptor antagonist (IL-1Ra) genes in inflammatory bowel disease. Clin Exp Immunol. 1995 Nov;102(2):379–383. doi: 10.1111/j.1365-2249.1995.tb03793.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Briggs D. C., Donaldson P. T., Hayes P., Welsh K. I., Williams R., Neuberger J. M. A major histocompatibility complex class III allotype (C4B 2) associated with primary biliary cirrhosis (PBC). Tissue Antigens. 1987 Mar;29(3):141–145. doi: 10.1111/j.1399-0039.1987.tb01566.x. [DOI] [PubMed] [Google Scholar]
  8. Brind A. M., Bray G. P., Portmann B. C., Williams R. Prevalence and pattern of familial disease in primary biliary cirrhosis. Gut. 1995 Apr;36(4):615–617. doi: 10.1136/gut.36.4.615. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chohan M. R. Primary biliary cirrhosis in twin sisters. Gut. 1973 Mar;14(3):213–214. doi: 10.1136/gut.14.3.213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Danis V. A., Millington M., Hyland V. J., Grennan D. Cytokine production by normal human monocytes: inter-subject variation and relationship to an IL-1 receptor antagonist (IL-1Ra) gene polymorphism. Clin Exp Immunol. 1995 Feb;99(2):303–310. doi: 10.1111/j.1365-2249.1995.tb05549.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dinarello C. A. Biologic basis for interleukin-1 in disease. Blood. 1996 Mar 15;87(6):2095–2147. [PubMed] [Google Scholar]
  12. Donaldson P. T. TNF gene polymorphisms in primary biliary cirrhosis: a critical appraisal. J Hepatol. 1999 Aug;31(2):366–368. doi: 10.1016/s0168-8278(99)80238-4. [DOI] [PubMed] [Google Scholar]
  13. El-Omar E. M., Carrington M., Chow W. H., McColl K. E., Bream J. H., Young H. A., Herrera J., Lissowska J., Yuan C. C., Rothman N. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 2000 Mar 23;404(6776):398–402. doi: 10.1038/35006081. [DOI] [PubMed] [Google Scholar]
  14. Ercilla G., Parés A., Arriaga F., Bruguera M., Castillo R., Rodés J., Vives J. Primary biliary cirrhosis associated with HLA-DRw3. Tissue Antigens. 1979 Nov;14(5):449–452. doi: 10.1111/j.1399-0039.1979.tb00874.x. [DOI] [PubMed] [Google Scholar]
  15. Gores G. J., Moore S. B., Fisher L. D., Powell F. C., Dickson E. R. Primary biliary cirrhosis: associations with class II major histocompatibility complex antigens. Hepatology. 1987 Sep-Oct;7(5):889–892. doi: 10.1002/hep.1840070516. [DOI] [PubMed] [Google Scholar]
  16. Goulis J., Leandro G., Burroughs A. K. Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis. Lancet. 1999 Sep 25;354(9184):1053–1060. doi: 10.1016/S0140-6736(98)11293-X. [DOI] [PubMed] [Google Scholar]
  17. Gregory W. L., Mehal W., Dunn A. N., Cavanagh G., Chapman R., Fleming K. A., Daly A. K., Idle J. R., James O. F., Bassendine M. F. Primary biliary cirrhosis: contribution of HLA class II allele DR8. Q J Med. 1993 Jun;86(6):393–399. [PubMed] [Google Scholar]
  18. Hurme M., Santtila S. IL-1 receptor antagonist (IL-1Ra) plasma levels are co-ordinately regulated by both IL-1Ra and IL-1beta genes. Eur J Immunol. 1998 Aug;28(8):2598–2602. doi: 10.1002/(SICI)1521-4141(199808)28:08<2598::AID-IMMU2598>3.0.CO;2-K. [DOI] [PubMed] [Google Scholar]
  19. James O. F., Bhopal R., Howel D., Gray J., Burt A. D., Metcalf J. V. Primary biliary cirrhosis once rare, now common in the United Kingdom? Hepatology. 1999 Aug;30(2):390–394. doi: 10.1002/hep.510300213. [DOI] [PubMed] [Google Scholar]
  20. Johnston D. E., Kaplan M. M., Miller K. B., Connors C. M., Milford E. L. Histocompatibility antigens in primary biliary cirrhosis. Am J Gastroenterol. 1987 Nov;82(11):1127–1129. [PubMed] [Google Scholar]
  21. Jones D. E., Watt F. E., Grove J., Newton J. L., Daly A. K., Gregory W. L., Day C. P., James O. F., Bassendine M. F. Tumour necrosis factor-alpha promoter polymorphisms in primary biliary cirrhosis. J Hepatol. 1999 Feb;30(2):232–236. doi: 10.1016/s0168-8278(99)80067-1. [DOI] [PubMed] [Google Scholar]
  22. Jones D. E., Watt F. E., Metcalf J. V., Bassendine M. F., James O. F. Familial primary biliary cirrhosis reassessed: a geographically-based population study. J Hepatol. 1999 Mar;30(3):402–407. doi: 10.1016/s0168-8278(99)80097-x. [DOI] [PubMed] [Google Scholar]
  23. Kaplan M. M. Primary biliary cirrhosis. N Engl J Med. 1996 Nov 21;335(21):1570–1580. doi: 10.1056/NEJM199611213352107. [DOI] [PubMed] [Google Scholar]
  24. Kershenobich D., Rojkind M., Quiroga A., Alcocer-Varela J. Effect of colchicine on lymphocyte and monocyte function and its relation to fibroblast proliferation in primary biliary cirrhosis. Hepatology. 1990 Feb;11(2):205–209. doi: 10.1002/hep.1840110208. [DOI] [PubMed] [Google Scholar]
  25. Kornman K. S., Crane A., Wang H. Y., di Giovine F. S., Newman M. G., Pirk F. W., Wilson T. G., Jr, Higginbottom F. L., Duff G. W. The interleukin-1 genotype as a severity factor in adult periodontal disease. J Clin Periodontol. 1997 Jan;24(1):72–77. doi: 10.1111/j.1600-051x.1997.tb01187.x. [DOI] [PubMed] [Google Scholar]
  26. Locke G. R., 3rd, Therneau T. M., Ludwig J., Dickson E. R., Lindor K. D. Time course of histological progression in primary biliary cirrhosis. Hepatology. 1996 Jan;23(1):52–56. doi: 10.1002/hep.510230108. [DOI] [PubMed] [Google Scholar]
  27. Louis E., Satsangi J., Roussomoustakaki M., Parkes M., Fanning G., Welsh K., Jewell D. Cytokine gene polymorphisms in inflammatory bowel disease. Gut. 1996 Nov;39(5):705–710. doi: 10.1136/gut.39.5.705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Manns M. P., Bremm A., Schneider P. M., Notghi A., Gerken G., Prager-Eberle M., Stradmann-Bellinghausen B., Meyer zum Büschenfelde K. H., Rittner C. HLA DRw8 and complement C4 deficiency as risk factors in primary biliary cirrhosis. Gastroenterology. 1991 Nov;101(5):1367–1373. doi: 10.1016/0016-5085(91)90090-8. [DOI] [PubMed] [Google Scholar]
  29. Mansfield J. C., Holden H., Tarlow J. K., Di Giovine F. S., McDowell T. L., Wilson A. G., Holdsworth C. D., Duff G. W. Novel genetic association between ulcerative colitis and the anti-inflammatory cytokine interleukin-1 receptor antagonist. Gastroenterology. 1994 Mar;106(3):637–642. doi: 10.1016/0016-5085(94)90696-3. [DOI] [PubMed] [Google Scholar]
  30. Metcalf J. V., Mitchison H. C., Palmer J. M., Jones D. E., Bassendine M. F., James O. F. Natural history of early primary biliary cirrhosis. Lancet. 1996 Nov 23;348(9039):1399–1402. doi: 10.1016/S0140-6736(96)04410-8. [DOI] [PubMed] [Google Scholar]
  31. Miyamori H., Kato Y., Kobayashi K., Hattori N. HLA antigens in Japanese patients with primary biliary cirrhosis and autoimmune hepatitis. Digestion. 1983;26(4):213–217. doi: 10.1159/000198892. [DOI] [PubMed] [Google Scholar]
  32. Nemetz A., Nosti-Escanilla M. P., Molnár T., Köpe A., Kovács A., Fehér J., Tulassay Z., Nagy F., García-González M. A., Peña A. S. IL1B gene polymorphisms influence the course and severity of inflammatory bowel disease. Immunogenetics. 1999 Jun;49(6):527–531. doi: 10.1007/s002510050530. [DOI] [PubMed] [Google Scholar]
  33. Pociot F., Mølvig J., Wogensen L., Worsaae H., Nerup J. A TaqI polymorphism in the human interleukin-1 beta (IL-1 beta) gene correlates with IL-1 beta secretion in vitro. Eur J Clin Invest. 1992 Jun;22(6):396–402. doi: 10.1111/j.1365-2362.1992.tb01480.x. [DOI] [PubMed] [Google Scholar]
  34. Santtila S., Savinainen K., Hurme M. Presence of the IL-1RA allele 2 (IL1RN*2) is associated with enhanced IL-1beta production in vitro. Scand J Immunol. 1998 Mar;47(3):195–198. doi: 10.1046/j.1365-3083.1998.00300.x. [DOI] [PubMed] [Google Scholar]
  35. Seki T., Kiyosawa K., Ota M., Furuta S., Fukushima H., Tanaka E., Yoshizawa K., Kumagai T., Mizuki N., Ando A. Association of primary biliary cirrhosis with human leukocyte antigen DPB1*0501 in Japanese patients. Hepatology. 1993 Jul;18(1):73–78. [PubMed] [Google Scholar]
  36. Sherlock S., Scheuer P. J. The presentation and diagnosis of 100 patients with primary biliary cirrhosis. N Engl J Med. 1973 Sep 27;289(13):674–678. doi: 10.1056/NEJM197309272891306. [DOI] [PubMed] [Google Scholar]
  37. Svejgaard A., Ryder L. P. HLA and disease associations: detecting the strongest association. Tissue Antigens. 1994 Jan;43(1):18–27. doi: 10.1111/j.1399-0039.1994.tb02291.x. [DOI] [PubMed] [Google Scholar]
  38. Tarlow J. K., Blakemore A. I., Lennard A., Solari R., Hughes H. N., Steinkasserer A., Duff G. W. Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat. Hum Genet. 1993 May;91(4):403–404. doi: 10.1007/BF00217368. [DOI] [PubMed] [Google Scholar]
  39. Underhill J., Donaldson P., Bray G., Doherty D., Portmann B., Williams R. Susceptibility to primary biliary cirrhosis is associated with the HLA-DR8-DQB1*0402 haplotype. Hepatology. 1992 Dec;16(6):1404–1408. doi: 10.1002/hep.1840160616. [DOI] [PubMed] [Google Scholar]

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